(a) Field
The present invention relates to novel amide compounds and their use as anti-tumoral and pro-apoptotic agents. The invention includes the use of such compounds in medicine, in relation to cancer disease, inflammatory diseases, neuronal diseases, parasite infections (e.g., Plasmodium infection), as well as other diseases where an inhibition of HDAC6 is responsive, and the pharmaceutical composition containing such compounds.
(b) Related Prior Art
Histone deacetylases have been biological targets of medicinal interest (see U.S. Pat. No. 7,250,504; U.S. Pat. No. 6,777,217; U.S. Published Application 20050287629). Post-translational modification of proteins through acetylation and deacetylation of lysine residues plays a critical role in regulating cellular functions. HDACs are zinc hydrolases that modulate gene expression through deacetylation of the N-acetyl-lysine residues of histone proteins and other transcriptional regulators. HDACs participate in cellular pathways that control cell shape and differentiation.
Vorinostat, originally known as SAHA (suberoylanilide hydroxamic acid), was the first-in-class small molecule hydroxamate derivative HDACi which has been approved by the FDA to treat a rare cancer, cutaneous T-cell lymphoma. SAHA is a potent non-selective HDACi inhibiting classes I and II as the vast majority of HDAC inhibitors currently in clinical trials.
Some clinical trials involving combination therapies have been conducted, to assess the efficacy of broad spectrum HDACi in combination with standard chemotherapeutic agents, (e.g., docetaxel and vorinostat), in patients with advanced and relapsed lung, bladder, or prostate cancer.
There is increasing evidence that HDAC6 plays a role in cancer cells and may be a target for drug development. HDAC6 presents the unique feature to possess two functional catalytic deacetylase domains and a carboxy terminal binding-of-ubiquitin zinc finger domain. Targeted inhibition of HDAC6 provokes acetylation of HSP90 and disruption of its chaperone function with its client proteins Bcr-Abl leading to antimetastatic and antiangiogenic effects, potential involvement of HDAC6 may also be potentially involved in the development of metastasis originating from breast cancer. HDAC6 inhibition has also been reported to be strongly involved in neuroprotection.
In summary, extensive evidence supports the potential for HDAC6 inhibitors in treatment of a variety of disorders and diseases, such as cancers and CNS diseases and degenerative conditions.
In the present invention, a novel series of heterocyclic compounds as potent HDAC6 inhibitors is disclosed, along with their potential uses as therapeutic agents.